The present invention is related to chemical processes and intermediates. More particularly, it is concerned with certain novel 5,6-substituted-2,4-quinazolinediamines and an improved process for preparing the compounds.
The compound 5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]-2,4-quinazolinediamine, known also by its trivial name timetrexate, is one of an important class of substituted 2,4-quinazolinediamines which are active folic acid antagonists possessing both antimalarial and anti-tumor activity. [See E. Elslager et al., J. Med. Chem., 26: 1753-1760 (1983)].
These antifolate drugs are presently generally prepared by the reductive coupling of the appropriately substituted benzeneamine with the appropriately substituted 6-cyano-2,4-quinazolinediamine. The 2,4-diaminoquinazolines required for this process have usually been prepared by a lengthy process which involves amination of the corresponding 2,4-dichloroquinazolines or by reaction of substituted o-aminobenzonitriles with dicyandiamide or cyanamide. [W. L. F. Armarego, "The Chemistry of Heterocyclic Compounds, Fused Pyrimidine. Part I. Quinazolines," Interscience, New York, 1967, pp. 330-332.]
Neither of these routes, however, is useful for the preparation of the substituted 6-cyano-2,4-quinazolinediamines which are necessary for the preparation of trimetrexate and related antifolate drugs via the convenient reductive coupling method.
J. Davoll et al., J. Chem. Soc., Section C, (1970) 997-1002 disclose a route for preparing the desired substituted 6-cyano-2,4-quinazolinediamines involving a multi-step synthesis which begins with the substituted 6-nitro-2,4-quinazolinediamines; proceeds through reduction to the substituted 2,4,6-triaminoquinazolines; and then through diazotization of the "aromatic" 6-amino-substituent and treatment with cuprous cyanide.
The various methods disclosed in the literature for preparing the substituted 6-cyano-2,4-quinazolinediamines required for the synthesis of trimetrexate and its analogues, require a large number of steps, with the attendant lower overall yields and increased cost. There has thus been a need for a process for the production of 5,6-substituted-2,4-quinazolinediamines which are useful in the production of trimetrexate and related antifolate compounds which overcomes these disadvantages.